2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives

a technology of benzo which is applied in the field of benzoic acid and amide derivatives of anthranilic acids, can solve the problems of mitogenic signals within the cell, and achieve the effect of reducing the number of mitogenic signals

Inactive Publication Date: 2006-03-28
WARNER-LAMBERT CO
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]This invention provides 4-bromo and 4-iodo phenylamino benzoic acid derivatives which are selective MEK kinase inhibitors and as such are useful for treating proliferative diseases such as cancer, psoriasis, and restenosis. The compounds are defined by Formula I

Problems solved by technology

Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell.

Method used

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  • 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives
  • 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives
  • 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives

Examples

Experimental program
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Effect test

example 1

4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic Acid

[0039]To a stirring solution comprised of 3.16 g (0.0133 mol) of 2-amino-5-iodotoluene in 5 mL of tetrahydrofuran at −78° C. was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran / heptane / ethenylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature it was stirred for 2 days. The reaction mixture was concentrated. Aqueous HCl (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO4) and then boiled over a steambath to low volume and cooled to room temperature. The off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76° C.; ca. 10 mm of Hg...

examples 2-30

[0041]By following the general procedure of Example 1, the following benzoic acids and salts were prepared:

[0042]

ExampleNo.CompoundMP ° C. 23,4,5-Trifluoro-2-(4-iodo-2-methyl-206-210phenylamino)-benzoic acid 33,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-240.5-244.5benzoic acid 45-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-259.5-262  phenylamino)-benzoic acid 55-Chloro-2-(2-chloro-4-iodo-phenylamino)-255-260benzoic acid 65-Chloro-2-(4-iodo-2-methyl-phenylamino)-234-238benzoic acid 7Sodium 5-Chloro-2-(4-iodo-2-methyl-310-320phenylamino)-benzoateDEC 85-Bromo-2-(4-iodo-2-methyl-phenylamino)-239.5-240  benzoic acid 92-(2-Chloro-4-iodo-phenylamino)-5-nitro-289-293benzoic acid104-Fluoro-2-(3-fluoro-4-iodo-2-methyl-233-235phenylamino)-benzoic acid112-(4-Iodo-2-methyl-phenylamino)-5-nitro-264-267benzoic acid122-(2-Fluoro-4-iodo-phenylamino)-5-nitro-256-258benzoic acid132-(4-Bromo-2-methyl-phenylamino)-4-fluoro-218.5-220  benzoic acid142-(2-Bromo-4-iodo-phenylamino)-5-nitro-285-288benzoic acidDEC1...

example 31

5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide

[0043]To a stirring solution comprised of 0.1020 g (0.2632 mmol) of 5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL (1.7 mmol) of ethanolamine, and 0.05 mL (0.29 mmol) of diisopropylethylamine in 5 mL of a 1:1 (v / v) tetrahydrofuran-dichloromethane solution was added 0.15 g (0.29 mmol) of solid PyBOP powder directly. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude residue was partitioned between ether (50 mL) and 10% aqueous hydrochloric acid (50 mL). The organic phase was washed with 10% aqueous sodium hydroxide (50 mL), dried (MgSO4) and concentrated in vacuo to afford a yellow-brown oil which was crystallized from hexanes-ether to afford 0.0831 g (73%) of a green-yellow powder; mp 120-121° C.;

[0044]1H NMR (400 MHz; CDCl3): δ 9.11 (s, 1H), 7.56 (d, 1H, J=1.4 Hz), 7.46-7.41 (m, 2H), 7.20 (dd, 1H, J=8.9, 2.4 Hz), 7.00 (t, 2H, J=9.6 Hz), 6.55 (...

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Abstract

Phenylamino benzoic acid, benzamides, and benzyl alcohol derivatives of the formula
    • where R1, R2, R3, R4, R5, and R6 are hydrogen or substituent groups such as alkyl, and where R7 is hydrogen or an organic radical, and Z is COOR7, tetrazolyl, CONR6R7, or CH2OR7, are potent inhibitors of MEK and, as such, are effective in treating cancer and other proliferative diseases such as inflammation, psoriasis and restenosis, as well as stroke, heart failure, and immunodeficiency disorders.

Description

[0001]This application is a Divisional application of U.S. Ser. No. 09 / 931,596 filed Aug. 16, 2001, now U.S. Pat. No. 6,492,363; which is a Divisional application of U.S. Ser. No. 09 / 462,319 filed Jan. 5, 2000, now U.S. Pat. No. 6,310,060; which was a 35 U.S.C. 371 application from PCT / US98 / 13105 filed Jun. 24, 1998, which claimed priority to U.S. Ser. No. 60 / 051,433, filed Jul. 1, 1997.FIELD OF THE INVENTION[0002]This invention provides benzoic acid and amide derivatives of anthranilic acids which inhibit certain dual specificity kinase enzymes involved in proliferative diseases such as cancer and restenosis.BACKGROUND OF THE INVENTION[0003]Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Cancer, for example, is commonly caused by a series of defects in these signaling proteins, resulting from a change either in their intrinsic activity or in their cellular concentrations. The cell may pro...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/5377A61K31/198A61K31/277A61K31/496C07C215/68C07C229/58C07C237/30C07C237/32C07C237/36C07C243/38C07C311/44C07D213/40C07D257/04C07D257/06C07D295/13C07D295/155C07D295/32C07D333/20
CPCC07C215/68C07D333/20C07C237/08C07C237/16C07C237/20C07C237/30C07C237/32C07C237/36C07C237/38C07C239/22C07C243/38C07C311/44C07D213/40C07D257/04C07D257/06C07D295/13C07D295/155C07D295/32C07C229/58C07C2101/02C07C2101/14C07C2601/02C07C2601/14
Inventor BARRETT, STEPHEN DOUGLASBRIDGES, ALEXANDER JAMESCODY, DONNA REYNOLDSDOHERTY, ANNETTE MARIANDUDLEY, DAVID THOMASSALTIEL, ALAN ROBERTSCHROEDER, MEL CONRADTECLE, HAILE
Owner WARNER-LAMBERT CO
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